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Blood, 15 November 2001, Vol. 98, No. 10, pp. 3042-3049
IMMUNOBIOLOGY
Receptor engagement by viral interleukin-6 encoded by Kaposi
sarcoma-associated herpesvirus
Yoshiyasu Aoki,
Masashi Narazaki,
Tadamitsu Kishimoto, and
Giovanna Tosato
From the Medicine Branch, National Cancer Institute,
National Institutes of Health, Bethesda, MD; Department of Molecular
Medicine, Osaka University Graduate School of Medicine, Suita, Osaka,
Japan.
Receptor usage by viral interleukin-6 (vIL-6), a virokine
encoded by Kaposi sarcoma- associated herpesvirus, is an issue
of controversy. Recently, the crystal structure of vIL-6 identified vIL-6 sites II and III as directly binding to glycoprotein (gp)130, the
common signal transducer for the IL-6 family of cytokines. Site I of
vIL-6, however, comprising the outward helical face of vIL-6, where
human IL-6 (hIL-6) would interact with the specific  -chain IL-6
receptor (IL-6R), is accessible and not occupied by gp130. This study
examined whether this unused vIL-6 surface is available for IL-6R
binding. By enzyme-linked immunosorbent assay, vIL-6 bound to soluble
gp130 (sgp130) but not to soluble IL-6R (sIL-6R). Using plasmon surface
resonance, vIL-6 bound to sgp130 with a dissociation constant of 2.5 µM, corresponding to 1000-fold lower affinity than that of
hIL-6/sIL-6R complex for gp130. sIL-6R neither bound to vIL-6 nor
affected vIL-6 binding to gp130. In bioassays, vIL-6 activity was
neutralized by 4 monoclonal antibodies (mAbs) recognizing a domain
within vIL-6 site I, mapped to the C-terminal part of the AB-loop and
the beginning of helix B. The homologous region in hIL-6 participates
in site I binding to IL-6R. In addition, binding of vIL-6 to sgp130 was
interfered with specifically by the 4 neutralizing anti-vIL-6 mAbs.
Based on the vIL-6 crystal structure, the vIL-6 neutralizing mAbs map outside the binding interface to gp130, suggesting that they either produce allosteric changes or block necessary conformational changes in
vIL-6 preceding its binding to gp130. These results document that vIL-6
does not bind IL-6R and suggest that conformational change may be
critical to vIL-6 function.
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